**3. Summary of evidence**

The COVID-19 pandemic has presented extremely challenging conditions for clinicians across the globe due to its infectivity, morbidity and mortality, characterized by the spread of lethal pneumonia in up to 15–20% of the cases [11]. The current therapeutic strategies for hospitalized patients are focused on the use of anti-inflammatory agents like corticosteroids, IL-6 inhibitors, antivirals agents like remdesivir, molnupiravir or a few monoclonal antibodies in combination with standard supportive care. There is still a need for more therapeutic alternatives for the hospitalized COVID-19 patients who are at risk of developing life-threatening complications such as ARDS and multiorgan dysfunction. In this context, the US FDA granted a EUA in November 2020 for baricitinib, an oral Janus Kinase inhibitor that inhibits cytokine release, to be used at a dose of 4 mg once daily in hospitalized adult patients with moderate to severe COVID-19 pneumonia in combination with remdesivir.. The FDA revised this EUA in July 2021 to allow the use of baricitinib alone (without remdesivir) for the treatment of COVID-19 in hospitalized adults and children ≥2 years of age who require supplemental oxygen, non-invasive or invasive mechanical ventilation, or ECMO [6]. Finally, in May 2022, the FDA has given full approval to baricitinib to be used for hospitalized COVID-19 adult patients as per the same conditions laid out in the EUA, while the use in children is still under the EUA.

In this chapter, we have attempted to meticulously unearth the evidence regarding the use of baricitinib as an anti-inflammatory drug for the treatment of COVID-19. Data from published observational and interventional studies reveal promising immunomodulatory and anti-inflammatory effects of baricitinib as monotherapy or in combination with other drugs in improving clinical and biochemical parameters, and other relevant disease markers in patients hospitalized with moderate to severe COVID-19. A lot of the initial evidence has come from observational studies on different drugs being tried in patients admitted in hospitals due to COVID-19, rather than the conventional gold standard RCTs; the published observational studies of different types outnumber the published interventional trials. Though the quality of evidence from observational studies (or NRSIs) may be relatively lower, the sheer number of parallel conclusions, supported by the evidence from the limited RCTs point to substantial benefits of using baricitinib in the treatment of COVID-19.

Among the multiple studies attempted to investigate clinical benefits of baricitinib in hospitalized COVID patients, some have compared the efficacy of baricitinib alone to the standard of care (antivirals, immunomodulators, protease inhibitors etc.), with different dosing regimens or loading dosages, and others have studied baricitinib as a part of a multi-drug pharmacological treatment regimens with different comparators. Despite the considerable heterogeneity in terms of study populations, sites, study designs, treatment regimens, significant study limitations, as well as the differences in summary measures, the evidence available is largely in favor of utility of the drug in COVID-19 in improving key clinical outcomes and/or biochemical or laboratory parameters, supported by an acceptable/satisfactory safety profile.

Among the 24 observational studies which include 16 retrospective cohort, 5 prospective cohort, and 3 case control studies, baricitinib has been compared to other drugs such as tocilizumab [28], used in various doses [23, 34], and therapeutic effects of loading dose changes or combination with other drugs have been assessed [24–29, 34] including IL-6 inhibitors, steroids and LMWHs like enoxaparin. The majority of the findings favor baricitinib due to its benefits in improving COVID-19 in terms of clinical, biochemical, and other disease characteristics. However, baricitinib

treatment did not result in a substantial reduction in mortality in some of the studies [24, 27, 28]. Few studies also revealed an increased incidence of adverse reactions such as mouth sores [23], infections [29], and thrombocytopenia [23, 28] with baricitinib treatment. But no study showed an inferiority of baricitinib in efficacy. Major drawbacks stem from the observational nature which introduces numerous methodological limitations and flaws along with biases, and the short duration of treatment and/ or follow up periods along with limited sample sizes. Key concerns in these studies include selection bias and confounding errors resulting from lack of randomization which were addressed to some extent in few studies; most could not.. Among the observational studies, 11 received a "fair" score and 13 received a "good" score when evaluated using the study quality evaluation tool [22], validated for evaluating observational research quality.

The findings of three large randomized controlled trials (RCTs) have been published. ACTT-2 results led to the EUA for baricitinib (with remdesivir) in hospitalized COVID-19 patients. The trial found that baricitinib + remdesivir (and standard of care) significantly reduced median time of recovery and mortality rate compared to control group (5.1 vs 7.8%) [47]. A similar reduction in mortality by 38.2% was also reported by Marconi et al.*.* in the experimental arm of oral baricitinib 4 mg plus standard treatment compared to controls who received placebo in addition to standard treatment (34). There was also improvement in participants' requirement for oxygen therapy especially in those who received high flow oxygen or for noninvasive ventilation. Encouragingly, fewer episodes of severe adverse events were seen in participants belonging to the baricitinib group compared to the standard of care. The ACTT-4 trial compared the combination of remdesivir with baricitinib or dexamethasone in hospitalized patients with COVID-19 requiring supplemental oxygen or non-invasive ventilation and showed that both combinations resulted in similar efficacy outcomes like mechanical ventilation-free survival by day 29, mortality and clinical status improvement. However, the baricitinib combination was found to be safer as dexamethasone was associated with significantly higher proportion of treatment-related adverse events, as well as severe or life-threatening adverse events [51]. The risk of bias was assessed using the risk of bias (ROB 2.0) tool [21]. All three RCTs were graded as having overall 'low risk of bias'. Besides these RCTs, results of three other interventional trials also support similar findings for the clinical utility of baricitinib among different COVID-19 patient populations.

As results from more ongoing RCTs get published, the evidence is likely to grow stronger.

#### **3.1 Ongoing clinical trials**

In addition to the published data, it is important to review the key ongoing registered clinical trials on use of baricitinib in treatment of COVID-19 to gain an understanding of the type of evidence expected in the future. There are currently multiple (>10) ongoing clinical trials evaluating the safety and efficacy of oral baricitinib alone or in combination for treatment of COVID-19 patients. **Table 2** provides key features of some of these registered trials, usually multicentric RCTs, listed on global clinical trial registries whose results have not been declared or published. One trial each is in phase III and IV, one is in phase II/III, four are in phase II, and one is in phase Ib/II.

Among the late phase trials, the TACTIC-R is a phase IV multi-arm platform trial proposed to be conducted at multiple centers across U.K. [52, 61]. It is a parallel 3-arm *Baricitinib in the Treatment of COVID-19 DOI: http://dx.doi.org/10.5772/intechopen.107269*



#### **Table 2.**

*Registered on-going clinical trials to evaluate the efficacy and safety of baricitinib in COVID-19 patients.*

(1:1:1) randomized trial evaluating baricitinib 4 mg OD and ravulizumab as a potential treatment for COVID-19 among hospitalized patients in comparison to standard treatment alone over a 14-day treatment period with follow-ups at day 28 and day 90 post-discharge. The safety and efficacy of different treatment arms will be assessed on a 7-point pulmonary scale, death, invasive mechanical ventilation, non-invasive ventilation or high flow oxygen, low flow oxygen, no oxygen, and status at discharge.

The phase III AMMURAVID RCT is proposed to be conducted across 21 study locations in Italy [53, 54] and is expected to enroll approximately 4000 participants with hospitalized COVID-19. The trial aims at evaluating the efficacy of remdesivir, baricitinib (4 mg), and remdesivir plus baricitinib vs the control arm (IV dexamethasone 6 mg × 10 days). The primary objective is minimization of progression of severe respiratory failure in COVID-19, as well as effect on immune response markers.

The BARI-COVID is an open-label, non-randomized trial [55] to investigate the efficacy of baric prospective cohort, and 3 case control studies itinib in combination with antiviral treatments in hospitalized patients with mild to moderate COVID-19. It is expected to enroll 200 participants in Italy. The experimental arm participants will be given 4 mg baricitinib orally in combination with lopinavir/ritonavir once daily. Participants in the control arm will be given antiviral treatment or hydroxychloroquine for 2 weeks. Comparison of proportion of participants requiring ICU hospitalization and assessment of CRP, IL-6, and TNF levels are the primary endpoints.

BREATH [56], a pilot treatment trial in Italy, is an open label study to evaluate the safety and efficacy of oral baricitinib 4 mg for 7 days in hospitalized patients with COVID-19 pneumonia. There are no comparator or control arms. Measurement of oxygenation impairment (PaO2/FiO2) and mortality on day 8 are endpoints. On 15th day, assessment of the participants will be done for median SpO2, number, types and severity of adverse events, biological assessments (level of various interleukins, TNF alpha, interferon gamma, viral load etc.) and rate of mortality.

Baricivid-19 [57], a phase II multicenter RCT in Italy, enrolled 126 patients (current status unclear) to compare baricitinib at a dose of 4 mg orally for 14 days (plus standard of care) against standard of care in hospitalized patients with COVID-19 pneumonia. The primary outcome is reduction in invasive ventilation at week 1 and 2, and there are multiple secondary endpoints like mortality (at 14, 28 days), time to invasive mechanical ventilation, length of hospital/ICU stays, toxicity.

Covid19COVINIB [58], an open label phase II RCT is proposed to enroll 165 patients to compare baricitinib and imatinib to supportive care therapy in patients with early COVID-19 pneumonia. The participants are designated to receive 400 mg OD of oral imatinib and 4 mg OD of oral baricitinib. Clinical improvement by at least two points on a 7-point ordinal scale is the primary end point, while safety (number of major side effects and early treatment cessation) and tolerability after 30 days are the secondary end points.

Another phase II trial is proposed in Canada, a non-randomized study on 800 adult patients hospitalized with moderate–severe COVID-19. Participants are to receive 2 mg oral baricitinib once day for 10 days, and the control arm would receive normal treatment. The primary objective of is to assess how long it takes for individuals to show clinical improvements in respiratory rate, fever, normal pulmonary function, and oxygen saturation.

The primary goal of the BARCOVID19 [60] trial in Spain is to ascertain the tolerability of baricitinib in oncohematological patients who have COVID-19 in phase I. It is anticipated that 136 participants will enroll in the trial. The aim of phase II of this trial is to establish if baricitinib (2–4 mg) reduces the inflammatory response caused by COVID-19, and prevents the development of severe ARDS in oncohematological patients as compared to other therapies given at the discretion of the investigator. Remdesivir or dexamethasone administration will be allowed if specific indications exist.

These ongoing clinical trials include different phases, randomized/nonrandomized, single/multicentric studies in geographically diverse locations, with different doses of baricitinib. Indications include the different disease severities, and assessments are at varying timepoints or intervals for a plethora of COVID-19 related outcomes. However, the recruiting status of most of these trials is uncertain. Nevertheless, if evidence comes from these studies, it can be expected to be robust. The TACTIC-R platform trial in the UK is especially interesting, being a phase IV study, as baricitinib is still under review for approval of use in COVID-19 by the EMA [9], and its approval for COVID-19 in UK could not be found. The NICE recently approved the medication for moderate to severe atopic dermatitis in March 2021 [62]. Current knowledge about the Omicron variant of the SARS-CoV-2 virus is relatively limited in terms of its transmissibility, severity of disease as well as effectiveness of currently available vaccines and treatments including the newer treatments [63]. It has raised further question marks over the adequacy of treatment options available for management of COVID-19, for all grades of disease, and the apprehension towards new waves of the pandemic persists.

#### **3.2 Current status of recommendation and limitations**

In terms of the current status of recommendations for baricitinib in COVID-19 treatment, the US NIH COVID-19 treatment guidelines (February 2022) include baricitinib as an add-on treatment option to corticosteroids and/or remdesivir for hospitalized adult patients requiring oxygen or non-invasive ventilation, with the strength of recommendation being weak in patients requiring supplemental oxygen, and moderate in patients needing high flow oxygen or non-invasive ventilation [64]. It is also recommended that baricitinib not be used in combination with tocilizumab as

both are potent immunosuppressants, leading to increased risk of infection. The WHO therapeutics and COVID-19 living guidelines have given strong recommendation (since January 2022) for the use of baricitinib as an alternative to IL-6 inhibitors in combination with corticosteroids in patients with severe or critical COVID-19, which includes hospitalized patients with SpO2 < 90%, signs of pneumonia, signs of severe respiratory distress, ARDS, sepsis /septic shock or requiring mechanical ventilation. However, baricitinib does not find a place as of now in the treatment recommendations/guidelines for COVID-19 from the UK-NICE or in countries like India, even though the drug has actually received an emergency approval in India [65, 66].

The qualitative synthesis of evidence that has been described in this chapter is quite comprehensive. But despite using the comprehensive WHO database of COVID research, a collection of most of the recognized electronic databases globally, for the literature search, there may still have been omissions especially from areas like gray or non-published literature. Majority of the studies finally selected were observationalmostly retrospective cohort, whereas only six published interventional studies could be found at the time of writing. In the hierarchy of evidence, observational studies are considered a relatively lower level of evidence. Non-uniformity of studies in terms of participants, outcomes, confounders etc. affects the external validity in the final analyses. As most of these studies are hospital based, a Berksonian bias is also likely to be present. The results of multiple clinical trials are not yet available as these are still ongoing or their current status is unknown.

## **4. Conclusion**

Multiple observational and interventional studies published till date show that baricitinib used alone or in combination with other drugs, as an add-on to standard of care, reduces the mortality and producessignificant clinical improvements in patients hospitalized with severe to moderate COVID-19, particularly those requiring high flow oxygen or ventilation. Approval of the drug by the FDA for treatment of COVID-19 among hospitalized adults, as well as the strong recommendation by the WHO for its use as an add-on alternative option to be used in combination with corticosteroids, accurately justifies its current status as an established therapeutic approach for COVID-19.
